A Ribosomopathy Reveals Decoding Defective Ribosomes Driving Human Dysmorphism

Area of Science:

• Genetics
• Molecular Biology
• Developmental Biology

Background:

• Ribosomal protein (RP) gene mutations are linked to bone marrow failure, often by slowing protein synthesis.
• The RPS23 gene, encoding ribosomal protein uS12, has not been previously associated with human disease.

Purpose of the Study:

• To investigate the role of de novo missense mutations in the RPS23 gene in individuals with developmental disorders.
• To elucidate the molecular mechanisms by which RPS23 mutations lead to disease phenotypes.

Main Methods:

• Genetic sequencing to identify de novo mutations in RPS23.
• Analysis of cellular phenotypes, including ribosomal subunit biogenesis, protein synthesis rates, translation accuracy, and oxidative stress sensitivity.

Main Results:

• Identified de novo missense mutations in RPS23 in two unrelated individuals with microcephaly, hearing loss, and dysmorphic features.
• One mutation impaired OGFOD1-dependent hydroxylation, blocking 40S ribosomal subunit formation. The other destabilized uS12, hindering 40S subunit biogenesis.
• Mutations impaired mRNA translation accuracy and increased oxidative stress sensitivity, without affecting translation rate.

Conclusions:

• These findings identify a novel ribosomopathy associated with uS12 mutations.
• Mechanisms differ from RP mutations causing hematopoietic disorders, highlighting distinct roles of ribosomal proteins in development versus hematopoiesis.